mRNA Expression Levels of PGC-1α in a Transgenic and a Toxin Model of Huntington’s Disease

Török, Rita; Kónya, Júlia Anna; Zádori, Dénes; Veres, Gábor; Szalárdy, Levente; Vécsei, László; Klivényi, Péter

doi:10.1007/s10571-014-0124-z

Cited by 15 publications

(30 citation statements)

References 41 publications

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“…It would be interesting to test these same PGC-1␣dependent transcripts in the striatum or substantia nigra of these PD models. In addition, polymorphisms in NRF-1 itself are able to influence age of onset in HD (Taherzadeh-Fard et al, 2011). Our previous studies have shown that NRF-1 is a potential mediator of PGC-1␣-dependent regulation of both Nefh and Cplx1 in the cortex (McMeekin et al, 2016) and enrichment of NRF-1 binding sites has been reported in the promoter region of Nefh by CHIP-seq (Satoh et al, 2013).…”

Section: Discussionmentioning

confidence: 94%

“…Reductions in the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1␣ (PGC-1␣) are thought to be a key factor in the progression of multiple neurological disorders, including Huntington's disease (HD). Polymorphisms in the ge ne encoding PGC-1␣ (Taherzadeh-Fard et al, 2009;Weydt et al, , 2014Ramos et al, 2012) and polymorphisms in PGC-1␣-interacting transcription factors and downstream genes are genetic modifiers of disease progression (Taherzadeh-Fard et al, 2011). These data indicate that dysfunction in PGC-1␣-dependent transcription may contribute to disease pathophysiology.…”

Section: Introductionmentioning

confidence: 92%

“…MSNs are the most affected neuronal population in HD (Ehrlich, 2012) and mutant huntingtin (mHtt)-mediated impairment in PGC-1␣-dependent transcription in this population could contribute to their vulnerability. Animals lacking fulllength or C-terminal expression of PGC-1␣ have vacuolizations throughout the brain, with severity being highest in the striatum (Lin et al, 2004;Leone et al, 2005;Lucas et al, 2012;Szalardy et al, 2013). This phenotype mirrors that seen in genetic mouse models of HD subjected to energy deprivation (Chaturvedi et al, 2010).…”

Section: Introductionmentioning

confidence: 97%

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Cell-Specific Deletion of PGC-1α from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment

McMeekin

Li²,

Fox

et al. 2018

J. Neurosci.

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Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is associated with neurodegeneration in diseases such as Huntington's disease (D). Polymorphisms in the PGC-1α gene modify HD progression and PGC-1α expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1α nor the contribution of PGC-1α deficiency to motor dysfunction is known. We identified novel, PGC-1α-dependent transcripts involved in RNA processing, signal transduction, and neuronal morphology and confirmed reductions in these transcripts in male and female mice lacking PGC-1α specifically in MSNs, indicating a cell-autonomous effect in this population. MSN-specific PGC-1α deletion caused reductions in previously identified neuronal and metabolic PGC-1α-dependent genes without causing striatal vacuolizations. Interestingly, these mice exhibited a hypoactivity with age, similar to several HD animal models. However, these newly identified PGC-1α-dependent genes were upregulated with disease severity and age in knock-in HD mouse models independent of changes in PGC-1α transcript, contrary to what would be predicted from a loss-of-function etiological mechanism. These data indicate that PGC-1α is necessary for MSN transcriptional homeostasis and function with age and that, whereas PGC-1α loss in MSNs does not replicate an HD-like phenocopy, its downstream genes are altered in a repeat-length and age-dependent fashion. Understanding the additive effects of PGC-1α gene functional variation and mutant huntingtin on transcription in this cell type may provide insight into the selective vulnerability of MSNs in HD. Reductions in peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-mediated transcription have been implicated in the pathogenesis of Huntington's disease (D). We show that, although PGC-1α-dependent transcription is necessary to maintain medium spiny neuron (MSN) function with age, its loss is insufficient to cause striatal atrophy in mice. We also highlight a set of genes that can serve as proxies for PGC-1α functional activity in the striatum for target engagement studies. Furthermore, we demonstrate that PGC-1α-dependent genes are upregulated in a dose- and age-dependent fashion in HD mouse models, contrary to what would be predicted from a loss-of-function etiological mechanism. However, given this role for PGC-1α in MSN transcriptional homeostasis, it is important to consider how genetic variation in PGC-1α could contribute to mutant-huntingtin-induced cell death and disease progression.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 97%

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Cell-Specific Deletion of PGC-1α from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment

McMeekin

Li²,

Fox

et al. 2018

J. Neurosci.

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“…However, higher cumulative doses (400-450 mg/kg) were widely used to induce measurable striatal lesions (Klivenyi et al, 2000(Klivenyi et al, , 2006. Accordingly, in a previous study we demonstrated a significant reduction in striatal neuronal density via the application of unbiased semiquantitative densitometric analysis by using a subacute dosing regimen with a cumulative dose of 500 mg/kg (Török et al, 2015).…”

Section: Introductionmentioning

confidence: 90%

“…The animals were randomly divided into two groups (n = 16 and n = 14, respectively). In the first group, 3-NP (SigmaAldrich, Saint Louis, MO, USA; dissolved in phosphate-buffered saline (PBS), pH adjusted to 7.4) was administered in a subacute dosing regimen as reported previously (Török et al, 2015), with twice daily intraperitoneal (i.p.) injections (50 mg/kg each) for 5 consecutive days.…”

Section: Animals and 3-np Treatmentmentioning

confidence: 99%

Central nervous system-specific alterations in the tryptophan metabolism in the 3-nitropropionic acid model of Huntington's disease

Veres

Molnár

Zádori

et al. 2015

Pharmacology Biochemistry and Behavior

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Experiments on human samples and on genetic animal models of Huntington's disease (HD) suggest that a number of neuroactive metabolites in the kynurenine (KYN) pathway (KP) of the tryptophan (TRP) catabolism may play a role in the development of HD. Our goal in this study was to assess the concentrations of TRP, KYN, kynurenic acid and 3-hydroxykynurenine (3-OHK) in the serum and brain of 5-month-old C57Bl/6 mice in the widely used 3-nitropropionic acid (3-NP) toxin model of HD. We additionally investigated the behavioral changes through open-field, rotarod and Y-maze tests. Our findings revealed an increased TRP catabolism via the KP as reflected by elevated KYN/TRP ratios in the striatum, hippocampus, cerebellum and brainstem. As regards the other examined metabolites of KP, we found only a significant decrease in the 3-OHK level in the cerebellum of the 3-NP-treated mice. The open-field and rotarod tests demonstrated that treatment with 3-NP resulted in a reduced motor ability, though this had almost totally disappeared a week after the last injection, similarly as observed previously in most murine 3-NP studies. The relevance of the alterations observed in our biochemical and behavioral analyses is discussed. We propose that the identified biochemical alterations could serve as applicable therapeutic endpoints in studies of drug effects on delayed-type neurodegeneration in a relatively fast and cost-effective toxin model of HD.

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Cerebellar Predominant Increase in mRNA Expression Levels of Sirt1 and Sirt3 Isoforms in a Transgenic Mouse Model of Huntington’s Disease

et al. 2020

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The potential role of Sirt1 and Sirt2 subtypes of Sirtuins (class III NAD +-dependent deacetylases) in the pathogenesis of Huntington's disease (HD) has been extensively studied yielding some controversial results. However, data regarding the involvement of Sirt3 and their variants in HD are considerably limited. The aim of this study was to assess the expression pattern of Sirt1 and three Sirt3 mRNA isoforms (Sirt3-M1/2/3) in the striatum, cortex and cerebellum in respect of the effect of gender, age and the presence of the transgene using the N171-82Q transgenic mouse model of HD. Striatal, cortical and cerebellar Sirt1-Fl and Sirt3-M1/2/3 mRNA levels were measured in 8, 12 and 16 weeks old N171-82Q transgenic mice and in their wild-type littermates. Regarding the striatum and cortex, the presence of the transgene resulted in a significant increase in Sirt3-M3 and Sirt1 mRNA levels, respectively, whereas in case of the cerebellum the transgene resulted in increased expression of all the assessed subtypes and isoforms. Aging exerted minor influence on Sirt mRNA expression levels, both in transgene carriers and in their wild-type littermates, and there was no interaction between the presence of the transgene and aging. Furthermore, there was no difference between genders. The unequivocal cerebellar Sirtuin activation with presumed compensatory role suggests that the cerebellum might be another key player in HD in addition to the most severely affected striatum. The mitochondrially acting Sirt3 may serve as an interesting novel therapeutic target in this deleterious condition.

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mRNA Expression Levels of PGC-1α in a Transgenic and a Toxin Model of Huntington’s Disease

Cited by 15 publications

References 41 publications

Cell-Specific Deletion of PGC-1α from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment

Cell-Specific Deletion of PGC-1α from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment

Central nervous system-specific alterations in the tryptophan metabolism in the 3-nitropropionic acid model of Huntington's disease

Cerebellar Predominant Increase in mRNA Expression Levels of Sirt1 and Sirt3 Isoforms in a Transgenic Mouse Model of Huntington’s Disease

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